Pre-clinical comparison of [DTPA0] octreotide, [DTPA0,Tyr3] octreotide and [DOTA0,Tyr3] octreotide as carriers for somatostatin receptor-targeted scintigraphy and radionuclide therapy.
We have evaluated the potential usefulness of radiolabelled [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide as radiopharmaceuticals for somatostatin receptor-targeted scintigraphy and radiotherapy. In vitro somatostatin receptor binding and in vivo metabolism in rats of the compounds were investigated in comparison with [111In-DTPA0] octreotide. Comparing different peptide-chelator constructs, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide were found to have a higher affinity than [DTPA0]octreotide for subtype 2 somatostatin receptors (sst2) in mouse AtT20 pituitary tumour cell membranes (all IC50 values obtained were in the low nanomolar range). In vivo studies in CA20948 tumor-bearing Lewis rats revealed a significantly higher uptake of both 111In-labelled [DOTA0,Tyr3]octreotide and [DTPA0,Tyr3]octreotide in sst2-expressing tissues than after injection of [111In-DTPA0]octreotide, showing that substitution of Tyr for Phe at position 3 in octreotide results in an increased affinity for its receptor and in a higher target tissue uptake. Uptake of 111In-labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide in pituitary, pancreas, adrenals and tumour was decreased to less than 7% of control by pre-treatment with 0.5 mg unlabelled octreotide/rat, indicating specific binding to sst2. Comparing different radionuclides, [90Y-DOTA0,Tyr3]octreotide had the highest uptake in sst2-positive organs, followed by the [111In-DOTA0,Tyr3]octreotide, whereas [DOTA0,125I-Try3]octreotide uptake was low compared to that of the other radiopharmaceuticals, when measured 24 hr after injection. Renal uptake of 111In-labelled [DTPA0]octreotide, [DTPA0,Tyr3]octreotide and [DOTA0,Tyr3]octreotide was reduced over 50% by an i.v. injection of 400 mg/kg D-lysine, whereas radioactivity in blood, pancreas and adrenals was not affected.
De Jong
M
M
Department of Nuclear Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands. dejong@nuge.azr.nl
Bakker
W H
WH
Breeman
W A
WA
Bernard
B F
BF
Hofland
L J
LJ
Visser
T J
TJ
Srinivasan
A
A
Schmidt
M
M
Béhé
M
M
Mäcke
H R
HR
Krenning
E P
EP
D000818:Animals; D004337:Drug Carriers; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes / Q000008:administration & dosage; D007457:Iodine Radioisotopes / Q000008:administration & dosage; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004369:Pentetic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D011868:Radioisotopes / Q000008:administration & dosage*; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes / Q000008:administration & dosage
D004337:Drug Carriers; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D015021:Yttrium Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004369:Pentetic Acid; D015282:Octreotide